It is known that calcium ions (Ca.sup.++) play vital roles in many cell processes. Calcium ions are particularly important to the function of cardiac tissue and vascular smooth muscle. The transition from the resting to the active state in the myocardium is initiated by cell depolarization which may be recorded as transmembrane action potential comprising a sharp peak caused by movement of sodium ions into the cell followed by a prolonged plateau during which calcium ions move into the cell. When intracellular concentration of calcium ions rises above about 10.sup.-7 M,, contraction occurs. The elevation of Ca.sup.++ concentration is believed to remove the inhibitory influence of the troponintropomyosin complex on the actin and myosin necessary for contraction.
The movement of sodium and calcium ions into the cells is considered to be through "channels" in the cell membrane. The extent of influx of Ca.sup.++ appears to be dependent on the number of channels open and the extent of their opening. The extent of opening appears to be dependent on membrane depolarization, phosphorylation of certain protein kinases, and activation of specific membrane receptors. The channels may be blocked by certain chemical compounds.
In view of the central role played by Ca.sup.++ in the electrophysiological and mechanical properties of the heart, and in the systemic and coronary arteries, the blocking of Ca.sup.++ channels can produce alterations in cardiovascular functions which can be advantageously employed in the treatment of a wide variety of cardiac disorders including cardiac arrhythmias, angina pectoris, arterial hypertension, hypertrophic obstructive cardiomyopathy and the like.
The effect of chemical compounds on the role played by Ca.sup.++ in cardiovascular functions is still being studied and suitable drugs are still being sought. Compounds which have been reported to be active as calcium entry blockers (sometimes referred to as calcium channel blockers) represent different types of chemical compounds. Thus, some of drug names and their chemical names are as follows: Nifedipine, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester; Verapamil, .alpha.-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-3,4-dimethox y-.alpha.-(1-methylethyl)benzeneacetonitrile; Prenylamine, N-(1-methyl-2-phenylethyl)-.alpha.-phenylbenzenepropanamine; Perhexiline, 2-(2,2-di-cyclohexylethyl)piperidine; Diltiazem, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1 ,5-benzothiazepin-4-(5H)-one; Cyproheptadine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine, and others. Representative literature disclosing the foregoing compounds in calcium entry blocker activity include D. A. Lowe et al., Br. J. Pharmacol. (1981) 74, 651, P. D. Henry, Am. J. Cardiology, 48 1047 (1980); L. D. Hillis, J. Cardiovasc. Med. 5(6) 583, 1980; and R. A. Janis et al., J. Med. Chem. 26(6), 775 (1983).
Two 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine compounds are identified in U.S. Pat. No. 2,985,660 directed to central stimulants and antispasmodic agents in animals. The compounds named in the patent are 5-(N-methyl-4-piperidyl)-5H-dibenzo[a,d]cycloheptene and 5-(4-piperidyl)-5H-dibenzo[a,d]cycloheptene which also may be named 4-(5H-dibenzo[a,d]-cyclohepten-5-yl)-1-methylpiperidine and 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, respectively. 4-(5H-Dibenzo[a,d]cyclohepten-5-yl)-1-methylpiperidine is also identified by structural formula in an article by E. L. Engelhardt et al., J. Med. Chem. 8, 829 (1965) concerning the antihistamic properties and antiserotonin properties of cyproheptadine compounds.
All of the compounds of the Engelhardt et al. reference having such activity are compounds in which the piperidine ring and the condensed benzene ring system are joined by a double bond. However, 4-(5H-Dibenzo[a,d]cyclohepten-5-yl)-1-methylpiperidine disclosed in the article as a reduction product is not reported to have properties similar to cyproheptadine. No pharmacological property is taught or suggested.
There has been discovered a new class of compounds related to the two aforementioned compounds which show properties suited for use as therapeutic agents for cardiovascular disorders acting pharmacologically as calcium entry blockers. Most of the members of this class of compounds are novel compounds not heretofore known for any pharmacological utility.